PROJECT SUMMARY Cognitive impairment due to Alzheimer's Disease (AD), AD-related dementias (ADRD), mild cognitive impairment (MCI), and/or age-related cognitive decline is a major public health problem that affects millions of older adults in the United States and worldwide. Recent studies show that ARDS and sepsis? acute illnesses characterized by systemic inflammation and multiple organ dysfunction?are risk factors for newly acquired MCI and moderate/severe cognitive impairment as well as acceleration of preexisting cognitive decline, yet a major knowledge gap exists regarding the pathophysiology of cognitive decline due to ARDS and sepsis. In the setting of these acute syndromes, systemic inflammation and endothelial dysfunction are known to contribute to organ failure, including brain dysfunction in the form of delirium, the duration of which predicts severity of persistent cognitive impairment months to years after the acute illness. Advances in our understanding of Alzheimer's Disease, ADRD, MCI, and other forms of neurodegenerative disease suggest that mechanisms known to contribute to these forms of dementia? namely neuroinflammation and blood-brain barrier disruption?may be at work in the brain during ARDS and sepsis, thereby contributing to ARDS/sepsis-related cognitive decline. We hypothesize that survivors of ARDS and sepsis at highest risk for long-term cognitive decline and dementia experience neuroinflammation (detectable using by positron emission tomography [PET] with [11C]PBR28) and blood-brain barrier disruption (detectable using dynamic contrast enhanced magnetic resonance imaging [DCE-MRI]). To test this hypothesis, we will complete the following aims: (1) determine whether a prolonged duration of delirium during ARDS and/or sepsis predicts increased neuroinflammation at hospital discharge (Aim 1A) and whether neuroinflammation at 3-month follow-up is associated with long- term cognitive impairment in ARDS/sepsis survivors (Aim 1B) and (2) determine whether a prolonged duration of delirium during ARDS and/or sepsis predicts blood-brain barrier disruption at hospital discharge (Aim 2A) and whether blood-brain barrier disruption at 3-month follow-up is associated with long-term cognitive impairment in ARDS/sepsis survivors (Aim 2B). To complete these aims, we will use the state-of-the-art facilities and expertise of the University of Pittsburgh PET Research Center and the Alzheimer?s Disease Research Center Neuroimaging Core to image and analyze participants in an ongoing, NHLBI-funded, prospective cohort study of ARDS and sepsis. By elucidating the pathophysiology of ARDS/sepsis-associated cognitive decline, this work will in due course lead to strategies that preserve cognitive function for both the millions who suffer from Alzheimer?s Disease and its related dementias as well as those with aging brains who develop ARDS and/or sepsis.